Nongenomic and genomic estrogen signaling pathways

Nongenomic and genomic estrogen signaling pathways. Endogenous estrogens including 17β-estradiol (E2) are nonselective activators of the three known estrogen receptors (ERs), ERα, ERβ and GPER. E2 activates nuclear ERs, inducing receptor dimerization, and binding of receptor dimers to the promoters of target genes. Alternatively, activated ERs modulate the function of other classes of transcription factors (TF) through protein–protein interactions. Subpopulations of ERs at the plasma membrane (mER) activated by E2 interact with adaptor proteins (adaptor) and signaling molecules such as c-Src, which mediates rapid signaling via PI3K/Akt and MAPK pathways. E2, or selective agonists such as G-1, or SERDs such as fulvestrant, or SERMs such as tamoxifen, also activate GPER, which is predominantly localized intracellularly. GPER activation stimulates cAMP production, calcium mobilization and c-Src, which activates matrix metalloproteinases (MMP). MMPs cleave pro-heparin-binding-epidermal growth factor (HB-EGF), releasing free HB-EGF that transactivates EGF receptors (EGFR). EGFR in turn activates MAPK and PI3K/Akt pathway, which can induce rapid (nongenomic) effects (X), or genomic effects regulating gene transcription. E2-mediated transcriptional regulation may involve phosphorylation (P) of ER or other TFs that may directly interact with ER, or bind independently of ER within the promoters of target genes.

Publication

The G protein-coupled estrogen receptor GPER in health and disease. () Eric R. Prossnitz, et al. Nat Rev Endocrinol. ;7(12):715-726. Figure: F2. All organisms Drosophila melanogaster Homo sapiens

Disease mentions